tbuckley/cabot-search huggingface dataset:
Treatment outcomes for newly diagnosed, treatment-naïve TP53-mutated acute myeloid leukemia: a systematic review and meta-analysis
Authors: Naval G. Daver, Shahed Iqbal, Camille Renard, Rebecca J. Chan, Ken Hasegawa, Hao Hu, Preston Tse, Jiajun Yan, Michael J. Zoratti, Feng Xie, Giridharan Ramsingh
Journal: Journal of Hematology & Oncology (2023)

Abstract Background TP53 mutations, which are present in 5% to 10% of patients with acute myeloid leukemia (AML), are associated with treatment resistance and poor outcomes. First-line therapies for TP53 -mutated ( TP53 m) AML consist of intensive chemotherapy (IC), hypomethylating agents (HMA), or venetoclax combined with HMA (VEN + HMA). Methods We conducted a systematic review and meta-analysis to describe and compare treatment outcomes in newly diagnosed treatment-naïve patients with TP53 m AML. Randomized controlled trials, single-arm trials, prospective observational studies, and retrospective studies were included that reported on complete remission (CR), CR with incomplete hematologic recovery (CRi), overall survival (OS), event-free survival (EFS), duration of response (DoR), and overall response rate (ORR) among patients with TP53 m AML receiving first-line treatment with IC, HMA, or VEN + HMA. Results Searches of EMBASE and MEDLINE identified 3006 abstracts, and 17 publications describing 12 studies met the inclusion criteria. Random-effects models were used to pool response rates, and time-related outcomes were analyzed with the median of medians method. IC was associated with the greatest CR rate of 43%, and CR rates were 33% for VEN + HMA and 13% for HMA. Rates of CR/CRi were comparable for IC (46%) and VEN + HMA (49%) but were lower for HMA (13%). Median OS was uniformly poor across treatments: IC, 6.5 months; VEN + HMA, 6.2 months; and HMA, 6.1 months. For IC, the EFS estimate was 3.7 months; EFS was not reported for VEN + HMA or HMA. The ORR was 41% for IC, 65% for VEN + HMA, and 47% for HMA. DoR was 3.5 months for IC, 5.0 months for VEN + HMA, and was not reported for HMA. Conclusions Despite improved responses seen with IC and VEN + HMA compared to HMA, survival was uniformly poor, and clinical benefits were limited across all treatments for patients with newly diagnosed, treatment-naïve TP53 m AML, demonstrating a significant need for improved treatment for this difficult-to-treat population.
Fluctuating selection and the determinants of genetic variation
Authors: Olivia L. Johnson, Raymond Tobler, Joshua M. Schmidt, Christian D. Huber
Journal: Trends in Genetics (2023)

Recent studies of cosmopolitan Drosophila populations have found hundreds to thousands of genetic loci with seasonally fluctuating allele frequencies, bringing temporally fluctuating selection to the forefront of the historical debate surrounding the maintenance of genetic variation in natural populations. Numerous mechanisms have been explored in this longstanding area of research, but these exciting empirical findings have prompted several recent theoretical and experimental studies that seek to better understand the drivers, dynamics, and genome-wide influence of fluctuating selection. In this review, we evaluate the latest evidence for multilocus fluctuating selection in Drosophila and other taxa, highlighting the role of potential genetic and ecological mechanisms in maintaining these loci and their impacts on neutral genetic variation.
Influence network model uncovers relations between biological processes and mutational signatures
Authors: Bayarbaatar Amgalan, Damian Wojtowicz, Yoo-Ah Kim, Teresa M. Przytycka
Journal: Genome Medicine (2023)

There has been a growing appreciation recently that mutagenic processes can be studied through the lenses of mutational signatures, which represent characteristic mutation patterns attributed to individual mutagens. However, the causal links between mutagens and observed mutation patterns as well as other types of interactions between mutagenic processes and molecular pathways are not fully understood, limiting the utility of mutational signatures. To gain insights into these relationships, we developed a network-based method, named GENESIGNET that constructs an influence network among genes and mutational signatures. The approach leverages sparse partial correlation among other statistical techniques to uncover dominant influence relations between the activities of network nodes. Applying GENESIGNET to cancer data sets, we uncovered important relations between mutational signatures and several cellular processes that can shed light on cancer-related processes. Our results are consistent with previous findings, such as the impact of homologous recombination deficiency on clustered APOBEC mutations in breast cancer. The network identified by GENESIGNET also suggest an interaction between APOBEC hypermutation and activation of regulatory T Cells (Tregs), as well as a relation between APOBEC mutations and changes in DNA conformation. GENESIGNET also exposed a possible link between the SBS8 signature of unknown etiology and the Nucleotide Excision Repair (NER) pathway. GENESIGNET provides a new and powerful method to reveal the relation between mutational signatures and gene expression. The GENESIGNET method was implemented in python, and installable package, source codes and the data sets used for and generated during this study are available at the Github site https://github.com/ncbi/GeneSigNet.
U-Sleep’s resilience to AASM guidelines
Authors: Luigi Fiorillo, Giuliana Monachino, Julia van der Meer, Marco Pesce, Jan D. Warncke, Markus H. Schmidt, Claudio L. A. Bassetti, Athina Tzovara, Paolo Favaro, Francesca D. Faraci
Journal: npj Digital Medicine (2023)

AASM guidelines are the result of decades of efforts aiming at standardizing sleep scoring procedure, with the final goal of sharing a worldwide common methodology. The guidelines cover several aspects from the technical/digital specifications, e.g., recommended EEG derivations, to detailed sleep scoring rules accordingly to age. Automated sleep scoring systems have always largely exploited the standards as fundamental guidelines. In this context, deep learning has demonstrated better performance compared to classical machine learning. Our present work shows that a deep learning-based sleep scoring algorithm may not need to fully exploit the clinical knowledge or to strictly adhere to the AASM guidelines. Specifically, we demonstrate that U-Sleep, a state-of-the-art sleep scoring algorithm, can be strong enough to solve the scoring task even using clinically non-recommended or non-conventional derivations, and with no need to exploit information about the chronological age of the subjects. We finally strengthen a well-known finding that using data from multiple data centers always results in a better performing model compared with training on a single cohort. Indeed, we show that this latter statement is still valid even by increasing the size and the heterogeneity of the single data cohort. In all our experiments we used 28528 polysomnography studies from 13 different clinical studies.
Integrated analysis of next generation sequencing minimal residual disease (MRD) and PET scan in transplant eligible myeloma patients
Authors: Rodrigo Fonseca, Mariano Arribas, Julia E. Wiedmeier-Nutor, Yael N. Kusne, Miguel González Vélez, Heidi E. Kosiorek, Richard J. Butterfield, Ilan R. Kirsch, Joseph R. Mikhael, A. Keith Stewart, Craig Reeder, Jeremy Larsen, P. Leif Bergsagel, Rafael Fonseca
Journal: Blood Cancer Journal (2023)

Abstract Minimal residual disease (MRD) assays allow response assessment in patients with multiple myeloma (MM), and negativity is associated with improved survival outcomes. The role of highly sensitive next generation sequencing (NGS) MRD in combination with functional imaging remains to be validated. We performed a retrospective analysis on MM patients who underwent frontline autologous stem cell transplant (ASCT). Patients were evaluated at day 100 post-ASCT with NGS-MRD and positron emission tomography (PET-CT). Patients with ≥ 2 MRD measurements were included in a secondary analysis for sequential measurements. 186 patients were included. At day 100, 45 (24.2%) patients achieved MRD negativity at a sensitivity threshold of 10 −6 . MRD negativity was the most predictive factor for longer time to next treatment (TTNT). Negativity rates did not differ according to MM subtype, R-ISS Stage nor cytogenetic risk. PET-CT and MRD had poor agreement, with high rates of PET-CT negativity in MRD-positive patients. Patients with sustained MRD negativity had longer TTNT, regardless of baseline risk characteristics. Our results show that the ability to measure deeper and sustainable responses distinguishes patients with better outcomes. Achieving MRD negativity was the strongest prognostic marker and could help guide therapy-related decisions and serve as a response marker for clinical trials.
Stable HIV decoy receptor expression after in vivo HSC transduction in mice and NHPs: Safety and efficacy in protection from SHIV
Authors: Chang Li, Anna Kate Anderson, Hongjie Wang, Sucheol Gil, Jiho Kim, Lishan Huang, Audrey Germond, Audrey Baldessari, Veronica Nelson, Katharine J. Bar, Christopher W. Peterson, John Bui, Hans-Peter Kiem, André Lieber
Journal: Molecular Therapy (2023)

(Molecular Therapy 31, 1059–1073; April 2023) In the originally published version of this article, Katharine J. Bar was not mentioned as a co-author. The SHIV studies were conducted by the Kiem lab, and Dr. Bar provided the virus stock. She has now been added as an author, and her contributions have been added to the author contributions section. This change has been reflected online, and the authors apologize for this error. Stable HIV decoy receptor expression after in vivo HSC transduction in mice and NHPs: Safety and efficacy in protection from SHIVLi et al.Molecular TherapyFebruary 8, 2023In BriefAfter in vivo HSC gene therapy, stable expression of the HIV/SHIV decoy receptor eCD4-Ig at therapeutically relevant levels were achieved in mice in mice and rhesus macaques. Intravenous challenge of a macaque with high-dose SHIV.D, eCD4-Ig greatly reduced peak virus levels in plasma and in important reservoir tissues. Full-Text PDF Open Access
Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616
Authors: Christie M. Ballantyne, Puja Banka, Gustavo Mendez, Raymundo Garcia, Julio Rosenstock, Anthony Rodgers, Geraldine Mendizabal, Yale Mitchel, Alberico L. Catapano
Journal: Journal of the American College of Cardiology (2023)

MK-0616 is an oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9) in development for the treatment of hypercholesterolemia.This Phase 2b, randomized, double-blind, placebo-controlled, multicenter trial aimed to evaluate the efficacy and safety of MK-0616 in participants with hypercholesterolemia.This trial was planned to include 375 adult participants with a wide range of atherosclerotic cardiovascular disease risk. Participants were assigned randomly (1:1:1:1:1 ratio) to MK-0616 (6, 12, 18, or 30 mg once daily) or matching placebo. The primary endpoints included percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) at Week 8 and the proportion of participants with adverse events (AEs) and study intervention discontinuations due to AEs; participants were monitored for AEs for an additional 8 weeks after the 8-week treatment period.Of the 381 participants randomized, 49% were female, and the median age was 62 years. Among 380 treated participants, all doses of MK-0616 demonstrated statistically significant (P < 0.001) differences in least squares mean percentage change in LDL-C from baseline to Week 8 vs placebo: -41.2% (6 mg), -55.7% (12 mg), -59.1% (18 mg), and -60.9% (30 mg). AEs occurred in a similar proportion of participants in the MK-0616 arms (39.5% to 43.4%) as placebo (44.0%). Discontinuations due to AEs occurred in 2 or fewer participants in any treatment group.MK-0616 demonstrated statistically significant and robust, dose-dependent placebo-adjusted reductions in LDL-C at Week 8 of up to 60.9% from baseline and was well tolerated during 8 weeks of treatment and an additional 8 weeks of follow-up. (A Study of the Efficacy and Safety of MK-0616 [Oral PCSK9 Inhibitor] in Adults With Hypercholesterolemia [MK-0616-008]; NCT05261126).
Randomized Trial of Anticoagulation Strategies for Noncritically Ill Patients Hospitalized With COVID-19
Authors: Gregg W. Stone, Michael E. Farkouh, Anuradha Lala, Elizabeth Tinuoye, Ovidiu Dressler, Pedro R. Moreno, Igor F. Palacios, Shaun G. Goodman, Rodrigo B. Esper, Alexandre Abizaid, Deepak Varade, Juan F. Betancur, Alejandro Ricalde, Gerardo Payro, José María Castellano, Ivan F.N. Hung, Girish N. Nadkarni, Gennaro Giustino, Lucas C. Godoy, Jason Feinman, Anton Camaj, Solomon W. Bienstock, Remo H.M. Furtado, Carlos Granada, Jessica Bustamante, Carlos Peyra, Johanna Contreras, Ruth Owen, Deepak L. Bhatt, Stuart J. Pocock, Valentin Fuster
Journal: Journal of the American College of Cardiology (2023)
Evinacumab in severe hypertriglyceridemia with or without lipoprotein lipase pathway mutations: a phase 2 randomized trial
Authors: Robert S. Rosenson, Daniel Gaudet, Christie M. Ballantyne, Seth J. Baum, Jean Bergeron, Erin E. Kershaw, Patrick M. Moriarty, Paolo Rubba, David C. Whitcomb, Poulabi Banerjee, Andrew Gewitz, Claudia Gonzaga-Jauregui, Jennifer McGinniss, Manish P. Ponda, Robert Pordy, Jian Zhao, Daniel J. Rader
Journal: Nature Medicine (2023)

Severe hypertriglyceridemia (sHTG) is an established risk factor for acute pancreatitis. Current therapeutic approaches for sHTG are often insufficient to reduce triglycerides and prevent acute pancreatitis. This phase 2 trial ( NCT03452228 ) evaluated evinacumab (angiopoietin-like 3 inhibitor) in three cohorts of patients with sHTG: cohort 1, familial chylomicronemia syndrome with bi-allelic loss-of-function lipoprotein lipase (LPL) pathway mutations (n = 17); cohort 2, multifactorial chylomicronemia syndrome with heterozygous loss-of-function LPL pathway mutations (n = 15); and cohort 3, multifactorial chylomicronemia syndrome without LPL pathway mutations (n = 19). Fifty-one patients (males, n = 27; females, n = 24) with a history of hospitalization for acute pancreatitis were randomized 2:1 to intravenous evinacumab 15 mg kg
Evolution of synchronous female bilateral breast cancers and response to treatment
Authors: Anne-Sophie Hamy, Judith Abécassis, Keltouma Driouch, Lauren Darrigues, Mathias Vandenbogaert, Cecile Laurent, Francois Zaccarini, Benjamin Sadacca, Myriam Delomenie, Enora Laas, Odette Mariani, Thanh Lam, Beatriz Grandal, Marick Laé, Ivan Bieche, Sophie Vacher, Jean-Yves Pierga, Etienne Brain, Celine Vallot, Judicael Hotton, Wilfrid Richer, Dario Rocha, Zakia Tariq, Veronique Becette, Didier Meseure, Laetitia Lesage, Anne Vincent-Salomon, Natalie Filmann, Jenny Furlanetto, Sibylle Loibl, Elise Dumas, Joshua J. Waterfall, Fabien Reyal
Journal: Nature Medicine (2023)

Abstract Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates ( n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors ( n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.
Autoantibodies against chemokines post-SARS-CoV-2 infection correlate with disease course
Authors: Jonathan Muri, Valentina Cecchinato, Andrea Cavalli, Akanksha A. Shanbhag, Milos Matkovic, Maira Biggiogero, Pier Andrea Maida, Jacques Moritz, Chiara Toscano, Elaheh Ghovehoud, Raffaello Furlan, Franca Barbic, Antonio Voza, Guendalina De Nadai, Carlo Cervia, Yves Zurbuchen, Patrick Taeschler, Lilly A. Murray, Gabriela Danelon-Sargenti, Simone Moro, Tao Gong, Pietro Piffaretti, Filippo Bianchini, Virginia Crivelli, Lucie Podešvová, Mattia Pedotti, David Jarrossay, Jacopo Sgrignani, Sylvia Thelen, Mario Uhr, Enos Bernasconi, Andri Rauch, Antonio Manzo, Adrian Ciurea, Marco B. L. Rocchi, Luca Varani, Bernhard Moser, Barbara Bottazzi, Marcus Thelen, Brian A. Fallon, Onur Boyman, Alberto Mantovani, Christian Garzoni, Alessandra Franzetti-Pellanda, Mariagrazia Uguccioni, Davide F. Robbiani
Journal: Nature Immunology (2023)

Abstract Infection with severe acute respiratory syndrome coronavirus 2 associates with diverse symptoms, which can persist for months. While antiviral antibodies are protective, those targeting interferons and other immune factors are associated with adverse coronavirus disease 2019 (COVID-19) outcomes. Here we discovered that antibodies against specific chemokines were omnipresent post-COVID-19, were associated with favorable disease outcome and negatively correlated with the development of long COVID at 1 yr post-infection. Chemokine antibodies were also present in HIV-1 infection and autoimmune disorders, but they targeted different chemokines compared with COVID-19. Monoclonal antibodies derived from COVID-19 convalescents that bound to the chemokine N-loop impaired cell migration. Given the role of chemokines in orchestrating immune cell trafficking, naturally arising chemokine antibodies may modulate the inflammatory response and thus bear therapeutic potential.
Accuracy and social motivations shape judgements of (mis)information
Authors: Steve Rathje, Jon Roozenbeek, Jay J. Van Bavel, Sander van der Linden
Journal: Nature Human Behaviour (2023)

The extent to which belief in (mis)information reflects lack of knowledge versus a lack of motivation to be accurate is unclear. Here, across four experiments (n = 3,364), we motivated US participants to be accurate by providing financial incentives for correct responses about the veracity of true and false political news headlines. Financial incentives improved accuracy and reduced partisan bias in judgements of headlines by about 30%, primarily by increasing the perceived accuracy of true news from the opposing party (d = 0.47). Incentivizing people to identify news that would be liked by their political allies, however, decreased accuracy. Replicating prior work, conservatives were less accurate at discerning true from false headlines than liberals, yet incentives closed the gap in accuracy between conservatives and liberals by 52%. A non-financial accuracy motivation intervention was also effective, suggesting that motivation-based interventions are scalable. Altogether, these results suggest that a substantial portion of people's judgements of the accuracy of news reflects motivational factors.
Complement activation and renal dysfunction in patients with acquired thrombotic thrombocytopenic purpura
Authors: Massimo Cugno, Ilaria Mancini, Dario Consonni, Valentina De Zan, Gianluigi Ardissino, Samantha Griffini, Elena Grovetti, Luigi Porcaro, Barbara Ferrari, Andrea Artoni, Flora Peyvandi
Journal: Blood (2023)
How I treat unique and difficult to manage cases of CAR T-cell therapy associated neurotoxicity
Authors: Bianca D Santomasso, Juliane Gust, Fabiana Perna
Journal: Blood (2023)

With growing indications for Chimeric Antigen Receptor (CAR) T-cell therapy, toxicity profiles are evolving. There is an urgent and unmet need for approaches to optimally manage emerging adverse events that extend beyond the standard paradigm of cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS). While management guidelines exist for ICANS, there is little guidance on how to approach patients with neurologic comorbidities, and how to manage rare neurotoxicity presentations such as CAR T-cell therapy related cerebral edema, severe motor complications or late onset neurotoxicity. Here, we present three scenarios of patients treated with CAR T-cells who develop unique types of neurotoxicity, and we describe an approach to evaluation and management based on experience because objective data are limited. The goal of this manuscript is to develop awareness of emerging and unusual complications, discuss treatment approaches and help institutions and health care providers establish frameworks to navigate how to best address unusual neurotoxicities to ultimately improve patient outcomes.
TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma
Authors: Jizhou Tan, Wenzhe Fan, Ting Liu, Bowen Zhu, Yafang Liu, Shutong Wang, Jian Wu, Jun Liu, Fan Zou, Jialiang Wei, Lingwei Liu, Xiaokai Zhang, Jialang Zhuang, Yi Wang, Haibiao Lin, Xianzhang Huang, Songling Chen, Ming Kuang, Jiaping Li
Journal: Journal of Hepatology (2023)
CDK7 controls E2F- and MYC-driven proliferative and metabolic vulnerabilities in multiple myeloma
Authors: Yao Yao, Jessica Fong Ng, Woojun Daniel Park, Mehmet K. Samur, Eugenio Morelli, Jessica Encinas, Zuzana Chyra, Yan Xu, Sanika Derebail, Charles B. Epstein, Behnam Nabet, Marta Chesi, Nathanael S Gray, Richard Young, Nicholas Kwiatkowski, Constantine S. Mitsiades, Kenneth C. Anderson, Charles Y. Lin, Nikhil C. Munshi, Mariateresa Fulciniti
Journal: Blood (2023)

Therapeutic targeting of CDK7 has proven beneficial in pre-clinical studies, yet the off-target effects of currently available CDK7 inhibitors make it difficult to pinpoint the exact mechanisms behind MM cell death mediated by CDK7 inhibition. Here, we show that CDK7 expression positively correlates with E2F and MYC transcriptional programs in multiple myeloma (MM) patient cells; and its selective targeting counteracts E2F activity via perturbation of the CDKs/Rb axis and impairs MYC-regulated metabolic gene signatures translating into defects in glycolysis and reduced levels of lactate production in MM cells. CDK7 inhibition using the covalent small molecule inhibitor YKL-5-124 elicits a strong therapeutic response with minimal effects on normal cells, and causes in vivo tumor regression increasing survival in several MM mouse models including a genetically engineered mouse model of MYC-dependent MM. Through its role as a critical cofactor and regulator of MYC and E2F activity, CDK7 is therefore a master regulator of oncogenic cellular programs supporting MM growth and survival, and a valuable therapeutic target providing rationale for development of YKL-5-124 for clinical use.
Prognostic Value of Preprocedural LV Global Longitudinal Strain for Post-TAVR-Related Morbidity and Mortality
Authors: Niels A. Stens, Odette van Iersel, Max J.P. Rooijakkers, Marleen H. van Wely, Robin Nijveldt, Esmée A. Bakker, Laura Rodwell, Anders L.D. Pedersen, Steen H. Poulsen, Didrik Kjønås, Jan Stassen, Jeroen J. Bax, Felix C. Tanner, Stamatios Lerakis, Sara Shimoni, Frédéric Poulin, Vera Ferreira, Vlatka Reskovic Luksic, Niels van Royen, Dick H.J. Thijssen
Journal: JACC. Cardiovascular imaging (2023)